C4 -amide substituted compounds and their use as therapeutic agents

ABSTRACT

The invention provides certain 5 and/or 8 substituted benzopyran, pyranopyridine or tetrahydroquinaline compounds having C 4  -amide substituent and processes for making them. The compounds described are useful in treating and/or preventing certain disorders.

This application is the national phase of POT/EP95/02,149, filed Jun.9,1995 issued as WO 95/34,547 on Dec. 21, 1995.

This invention relates to novel compounds, to processes for preparingthem, and to their use as therapeutic agents.

European Published Patent Application No. 0126311 discloses substitutedbenzopyran compounds having blood pressure lowering activity, including6-acetyl-trans-4-(4-fluorobenzoylamino)- 3,4-dihydro-2,2-dirmethyl-2H- 1-benzopyran-3-ol.

Also EP-A-0 376 524, EP-A-0 205 292, EP-A-0 250 077, EP-A-0 093 535,EP-A-0 150 202, EP-A-0 076 075 and WO/89/05808 (Beecham Group plc)describe certain benzopyran derivatives which possess anti-hypertensiveactivity.

EP-A-0 350 805 (Biersdorf), EP-A-0 277 611, EP-A-0 277612, EP-A-0 337179 and EP-A-0 355 565 (Hoechst Aktiengesellschaft); EP-A-0 466 131(Nissan Chemical Industries Ltd), EP-A-0339562 (YoshitomiPharmaceuticals) EP-A-415 065 (E. Merck) EP-A-450415 (Squibb),EP-A-0482934, EP-A-0296975, EPA 571822 (Daiichi Pharm.), JO-2004-791 andWO\89\07103 also describe certain benzopyran derivatives which arebelieved to possess anti-hypertensive activity.

EP-A-0 430 621 and EP-A-0 385 584 (Beecham Group plc) describe theresolution of certain intermediates useful in the preparation of thecompounds described in the above mentioned patent applications.

EP-A-0 139 992 (Beecham Group plc) describes certain benzopyranderivatives which have cis isomerism at position 3 and 4 which compoundsare described as possessing anti-hypertensive activity.

PCT/GB92/01045 (SmithKline Beecham plc; unpublished at the prioritydate), which describes certain fluorobenzoylamino benzopyrans,pyranopyridines and tetrahydronaphthalenes in which the 3 and 4 positionsubstituents are trans to each other. These compounds are described aspossessing inter alia anxiolytic and anti-convulsant activity.

It has now been surprisingly found that certain compounds of formula (I)(below) possess anti-convulsant activity, and are therefore believed tobe useful in the 30 treatment and/or prevention of epilepsy; thecompounds of formula (I) are also believed to have utility in thetreatment or prevention of anxiety, mania, depression, disordersassociated with a subarachnoid haemorrhage or neural shock, the effectsassociated with withdrawal from substances of abuse, Parkinson'sDisease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease,schizophrenia, OCD (obsessive compulsive disorder), panic disordersand/or agression.

Accordingly, the present invention provides a compound of formula (I) orpharmaceutically acceptable salt thereof: ##STR1## wherein: either Y isN and R₂ is hydrogen, or Y is C--R₁ ;

where:

either one of R₁ and R₂ is hydrogen and the other is selected from theclass of hydrogen, C₃₋₈ cycloalkyl, C₁₋₆ alkyl optionally interrupted byoxygen or substituted by hydroxy, C₁₋₆ alkoxy or substitutedaminocarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆ alkoxy, nitro, cyano, halo, trifluoromethyl, CF₃S, or a group CF₃ --A--, where A is --CF₂ --, --CO--, --CH₂ --, CH(OH),SO₂, SO, CH₂ --O, or CONH, or a group CF₂ H--A'--where A' is oxygen,sulphur, SO, SO₂, CF₂ or CFH; trifluoromethoxy, C₁₋₆ alkylsulphinyl,perfluoro C₂₋₆ alkylsulphonyl, C₁₋₆ alkylsulphonyl, C₁₋₆alkoxysulphinyl, C₁₋₆ alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl,heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy,arylsulphinyl, heteroarylsulphinyl, arylsulphonyl, heteroarylsulphonylin which any aromatic moiety is optionally substituted, C₁₋₆alkylcarbonylamino, C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkyl-thiocarbonyl,C₁₋₆ alkoxy-thiocarbonyl, C₁₋₆ alkyl-thiocarbonyloxy, 1-mercapto C₂₋₇alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, anyamino moiety being optionally substituted by one or two C₁₋₆ alkylgroups, or C₁₋₆ alkylsulphinylamino, C₁₋₆ alkylsulphonylamino,C₁₋₆alkoxysulphinylamino or C₁₋₆ alkoxysulphonylamino, or ethylenylterminally substituted by C₁₋₆ alkylcarbonyl, nitro or cyano, or--C(C₁₋₆ alkyl)NOH or --C(C₁₋₆ alkyl)NNH₂, or one of R₁ and R₂ is nitro,cyano or C₁₋₃ alkylcarbonyl and the other is halo, C₁₋₄ alkyl, methoxyor amino optionally substituted by one or two C₁₋₆ alkyl or by C₂₋₇alkanoyl; or R₁ and R₂ together are --(CH₂)₄ --; (CH₂)_(X) CO (CH₂)ywhere x is 0 to 3 and y is 0 to 3 with the proviso that x+y is at least2×; or --CH═CH--CH═CH--; or form an optionally substituted triazole oroxadiazole ring, or together form a group CONR^(C) CO where R^(C) ishydrogen, C₁₋₆ alkyl, aralkyl or heteroarylalkyl;

either Z is N only when Y is C--R₁ or Z is C--R^(a) when Y is N orC--R₁, wherein R^(a) is hydrogen, halogen, nitro C₁₋₄ alkylcarbonyl,C₁₋₄ alkyl; aryl C₁₋₄ alkyl, aryl C₁₋₄ alkenyl, heteroaryl C₁₋₄ alkyl orheteroaryl C₁₋₄ alkenyl, R^(b) is hydrogen, halogen, nitro;

C₁₋₄ alkylcarbonyl or C₁₋₄ alkyl with the proviso that R^(a) and R^(b)are not simultaneously hydrogen except in the case where one of R₁ andR₂ is nitro, cyano, or C₁₋₃ alkylcarbonyl and the other is halo or C₁₋₄alkyl; and in which any aryl or heteroaryl or alkyl moiety associatedwith R^(a) or R^(b) are optionally substituted; one of R₃ and R₄ ishydrogen or C₁₋₄ alkyl and the other is C₁₋₄ alkyl, CF₃ or CH₂ X^(a)where X^(a) is fluoro, chloro, bromo, iodo, C₁₋₄ alkoxy, hydroxy, C₁₋₄alkylcarbonyloxy, --S--C₁₋₄ alkyl, nitro, amino optionally substitutedby one or two C₁₋₄ alkyl groups; cyano or C₁₋₄ alkoxycarbonyl or R₃ andR₄ together are C₂₋₅ polymethylene optionally substituted by C₁₋₄ alkyl;

R₅ is C₁₋₆ alkylcarbonyloxy, benzoyloxy, ONO₂, benzyloxy, phenyloxy orC₁₋₆ alkoxy and R₆ and R₉ are hydrogen or R₅ is hydroxy and R₆ and R₉are independently hydrogen or C₁₋₂ alkyl;

R₇ is heteroaryl or phenyl; both of which are optionally substituted oneor more times independently with a group or atom selected from chloro,fluoro, bromo, iodo, nitro, amino optionally substituted once or twiceby C₁₋₄ alkyl, cyano, azido, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethoxy,trifluoromethyl; optionally substituted aryloxy or heteroaryloxy;

C₁₋₄ alkoxy substituted by one or more halogens (excludingtrifluoromethoxy);

amino substituted by C₁₋₄ alkanoyl, aroyl aryl phenylsulphonyl or C₁₋₄alkylsulphonyl;

C₁₋₄ alkyl substituted by one or more halogens (excludingtrifluoromethyl) or alkoxy;

phenylsulphonyl C₁₋₄ alkyl sulphonyl, aminosulphonyl in which the aminogroup is optionally substituted by C₁₋₄ alkyl;

CONH₂ in which the amino group is optionally substituted by C₁₋₄ alkyl;

R₈ is hydrogen; C₁₋₆ alkyl, OR_(c) or NHCOR₁₀ wherein R_(c) is hydrogen,C₁₋₆ alkyl, formyl, C₁₋₆ alkanoyl, aroyl or aryl-C₁₋₆ alkyl and R₁₀ ishydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, mono or di C₁₋₆ alkyl amino, amino,amino-C₁₋₆ alkyl, hydroxy-C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ acyloxy-C₁₋₆alkyl, C₁₋₆ alkoxycarbonyl-C₁₋₆ -alkyl, aryl or heteroaryl;

the R₈ -N-CO-R₇ group being cis or trans to the R₅ group;

and X is oxygen or NR₁₀ where R₁₀ is hydrogen or C₁₋₆ alkyl.

All C₁₋₆ alkyl or C₁₋₄ alkyl or alkyl containing groups in formula (I)are preferably selected from methyl, ethyl, n - and iso -propyl, n -,iso -, sec - and tert-butyl.

Suitable C₃₋₈ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Suitable halo substituents include fluoro, chloro, bromo and iodo.

Aryl whenever mentioned herein includes but is not limited to phenyl andnaphthyl.

Heteroaryl whenever mentioned herein includes a 5- or 6- memberedmonocyclic or 9- or 10- membered bicyclic of which 5- or 6- memberedmonocyclic heteroaryl is preferred. In addition, 5- or 6-memberedmonocyclic or 9- or 10-membered bicyclic heteroaryl preferably containsone, two or three heteroatoms which are selected from the class ofoxygen, nitrogen and sulphur and which, in the case of there being morethan one heteroatom, are the same or different. Examples of 5- or6-membered monocyclic heteroaryl containing one, two or threeheteroatoms which are selected from the class of oxygen, nitrogen andsulphur include furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyland thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazolyl andtriazolyl. Preferred examples of such groups include furanyl, thienyl,pyrryl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrryl, 2-and 3-thienyl, and 2-, 3- and 4-pyridyl. Examples of 9- or 10-memberedbicyclic heteroaryl containing one, two or three heteroatoms which areselected from the class of oxygen, nitrogen and sulphur includebenzofuranyl, benzothienyl, indolyl and indazolyl, quinolyl andisoquinolyl, and quinazolyl. Preferred examples of such groups include2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2-and 3-quinolyl.

Suitable examples of groups or atoms for optional substitutionespecially of aryl heteroaryl and alkyl moieties, especially associatedwith R^(a) and R^(b) include one, two or three substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy C₁₋₄ alkylcarbonyloxy, C₁₋₄ alkyl carbonyl, halo (such as fluoro, chloro, bromoand iodo), hydroxy, nitro, amino optionally substituted once or twice byC₁₋₄ alkyl, cyano and SO_(n) H, where n=0 to 2.

Preferably R₁ is acetyl.

Preferably R₂ is hydrogen, fluorine or methyl.

When Z is CR^(a), preferably R^(a) is hydrogen, iodo, bromo, nitro oracetyl.

Preferably R⁶ is hydrogen or acetyl.

Preferably R₃ and R₄ are both methyl.

Preferably R₅ is hydroxy and R₆ and R₉ are hydrogen.

It should be appreciated that when R₇ is phenyl optionally independentlysubstituted; this includes substitution by 1,2,3,4 or 5 groups or atomsattached to the phenyl ring. Preferably there are 1 or 2 groups or atomsattached to the phenyl ring. The groups or atoms may be in any positionaround the phenyl ring. Likewise, it should be appreciated that when R₇is heteroaryl optionally independently substituted; this includessubstituents at any vacant positions around the heteroaryl moiety.Preferably there are 1 or 2 groups or atoms around the heteroarylmoiety, most preferably there is one group or atom around the heteroarylmoiety.

Preferably R₇ is 2,3-or 4-fluorophenyl, phenyl, 2 or 3-chlorophenyl,2,3-dichlorophenyl, 2-trifluoromethylphenyl, 2-nitrophenyl,2-chloro-thiophen-3-yl, 3-chloro-thiophen-2-yl,2,5dichloro-thiophen-3-yl or 3-chloro-4-fluorophenyl.

Preferably R₈ is hydrogen.

Preferably X is oxygen.

It should be appreciated that the compounds of formula (I) may havechiral carbon atoms at positions in addition to positions 3 and 4 andtherefore may exist as enantiomers. The present invention extends toeach enantiomer and to mixtures thereof including racemates. It shouldfurther be appreciated that particular enantiomeric forms are preferredfor different utilities, thus for utilities other than sub-arachnoidhaemorrhage or neural shock the 3S, 4S or 3R, 4S enantiomers arepreferred, however, for sub-arachnoid haemorrhage or neural shock the3S, 4R enantiomers are preferred.

It should be appreciated that the compound of formula (I) or apharmaceutically acceptable salt thereof also includes solvates of suchcompounds, such as for example the hydrate.

The present invention further provides a compound of formula (I), or apharmaceutically acceptable salt thereof as hereinbefore defined whichexists predominantly in the 3S, 4S enantiomeric form.

It should be appreciated that the term "exists predominantly in the 3S,4S enantiomeric form" means that there is greater than 50% of the 3S, 4Senantiomer present compared to the 3R, 4R enantiomer.

More preferably there is greater than 60% of the 3S, 4S enantiomerpresent, yet more peferably greater than 70% of the 3S, 4S enantiomerpresence, even more preferably greater than 80% of the 3S, 4S enantiomerpresent and more preferably still greater than 90% of the 3S, 4Senantiomer present. Most preferably there is greater than 95% of the 3S,4S enantiomer compound to the 3R, 4R enantiomer. The same applies to the3R, 4S enantiomeric form.

Example of compounds of formula (I) are:

trans-6-Acetyl-4-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1 -benzopyran-3-ol;

trans-6-Acetyl-4-(2-chlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-pyrano2,3-b!pyridin-3-ol;

trans-6-Acetyl-4-(2,3-dichlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-pyrano 2, 3-b!pyridin-3-ol;

trans-6-Acetyl-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-8-nitro-2H-1-benzopyran-3-ol;

trans-8-Acetyl-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol;

trans-8-Bromo-4-(3-bromo-4-fluorobenzoylamino)-6-ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol;

trans-5-Acetyl-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol;

trans-6-Acetyl-4S-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3R-ol;

trans-8-Acetyl-4-(2-chlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol;

trans-8-Acetyl-4-(3-chlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzopyran-3-ol;

trans6-Acetyl-4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethyl)-2H-1-benzopyran-3-ol;

trans 6-Acetyl-4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethenyl)-2H-1-benzopyran-3-ol;

(±)-10-bromo-2,2-dimethyl-trans-4-(4-fluorobenzoylamino)-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno3,2-b!pyran-3-ol;

trans-3R,4S-6-Acetyl-4-(3-ethoxymethylbenzoylamino)-3-4-dihydro-8-iodo-2.2-dimethylbenxopb!pyran-3-ol;

trans-3R,4S-6-Acetyl-4-(3-Acetyloxymethylbenzoylamino)-3,4-dihydro-8-iodo-2,2dimethylbenzolb!pyran-3-ol;

trans-3R,4S-6-Acetyl-3,4-dihydro-4-(3-hydroxymethylbenzoylamino)-8-iodo-2,2-dimethylbenzob!pyran-3-ol;

(±)-2,2-dimethyl-trans-4-(3-chloro-4-fluorobenzoylamino-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno3,2-b! pyran-3-ol;

trans-6-Acetyl-3,4-dihydro-2,2-dimethyl-4S-(3-chlorobenzoylamino)-8-iodo-2H-benzob!pyran-3R-ol;

cis6-Acetyl-4S-(3-chlorobenzoylamino)-3,4-Dihydro-2,2-dimethyl-8-hydroxymethyl-2H-benzolb!pyran-3S-ol;

cis8-Acetoxymethyl-6-acetyl4S-(3-chlorobenzoylamino)-3,4dihydro-2,2-dimethyl-2H-benzob!pyran-3S-ol;

trans-6-Acetyl-4-(4-fluorobenzoylamino)-3,4dihydro-2,2,7-trimethyl-2H-1-benzopyran-3-oland

trans-6-Acetyl-7-fluoro-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.

Such compounds, solvates and pharmaceutically acceptable salt thereofare believed to be novel and form a preferred aspect of the presentinvention.

The administration to the mammal may be by way of oral or parenteraladministration.

An amount effective to treat the disorders hereinbefore describeddepends on the usual factors such as the nature and severity of thedisorders being treated and the weight of the mammal. However, a unitdose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, forexample an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20,30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doseswill normally be administered once or more than once per day, forexample 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day,such that the total daily dose is normally in the range, for a 70 kgadult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range ofapproximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, forexample 1 to 6 mg/kg/day.

It is greatly preferred that the compound of formula (I) is administeredin the form of a unit-dose composition, such as a unit dose oral, suchas sub-lingual, rectal, topical or parenteral (especially intravenous)composition.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories. Orally administrable compositions arepreferred, in particular shaped oral compositions, since they are moreconvenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

Oral formulations also include conventional sustained releaseformulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

The present invention further provides a pharmaceutical composition foruse in the treatment and/or prophylaxis of anxiety, mania, depression,disorders associated with a subarachnoid haemorrhage or neural shock,the effects associated with withdrawal from substances of abuse such ascocaine, nicotine, alcohol and benzodiazepines, disorders treatable orpreventable with anti-convulsive agents, such as epilepsy; Parkinson'sdisease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease,schizophrenia, OCD, panic disorders and/or agression which comprises acompound of formula (I) or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

The present invention also provides a method of treatment and/orprophylaxis of anxiety, mania, depression, disorders associated with asubarachnoid haemorrhage or neural shock, the effects associated withwithdrawal from substances of abuse such as cocaine, nicotine, alcoholand benzodiazepines, disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy; Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease,schizophrenia, OCD, panic disorders and/or agression, comprisingadministering to the sufferer in need thereof an effective orprophylactic amount of a compound of formula (I) pharmaceuticallyacceptable salt thereof.

In a further aspect the invention provides the use of a compound offormula (I) including or a pharmaceutically acceptable salt thereof, forthe manufacture of a medicament for the treatment and/or prophylaxis ofanxiety, mania, depression, disorders associated with a subarachnoidhaemorrhage or neural shock, the effects associated with withdrawal fromsubstances of abuse such as cocaine, nicotine, alcohol andbenzodiazepines, disorders treatable or preventable with anti-convulsiveagents, such as epilepsy; Parkinson's disease, psychosis, migraine,cerebral ischaemia, Alzheimer's disease, schizophrenia, OCD, panicdisorders and/or agression.

In a further aspect the present invention provides a pharmaceuticalcomposition containing a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

In a further aspect the invention provides the use of a compound offormula (I) a pharmaceutically acceptable salt thereof as a therapeuticagent, in particular for the treatment and/or prophylaxis of anxiety,mania, depression, disorders associated with a sub-arachnoidhaemorrhage, neural shock, the effects associated with withdrawal fromsubstances of abuse such as cocaine, nicotine, alcohol andbenzodiazepines; disorders treatable or preventable with anti-convulsiveagents, such as epilepsy; Parkinson's disease, pychosis, migraine,cerebral ischaemia, Alzheimer's disease, schizophrenia, OCD, panicdisorders and/or agression.

Such compositions may be prepared in the manner as hereinbeforedescribed.

Generally, the trans compounds of formula (I) may be prepared accordingto or analogously to the procedures described in EP-0126311, EP-0376524,EP-205292, EP-0250077, EP-0093535, EP-0150202, EP-0076075, WO/89/05808,EP-0350805, EP-0277611, EP-0277612, EP-0337179, EP-0339562, EP-0355565,EP-A-415 065 (E. Merck), EP-A-450 415 (Squibb) EP-0466131, EP-A-0482934,EP-A-0296975, JO-2004-791 and WO\89\07103.

The cis compounds may be prepared by procedures generally described inor analogous to those described in EP-A-0139992 or from thecorresponding trans compounds.

This cis compounds of formula (I) may also be prepared according to theprocedures described by G. Burrell et al, Tet. Letters, 31, 3649-3652(1990) or by the procedures described by U. Quast and E. Villhauer, Eur.J. Pharmacol, Molecular Pharmacology Section 245, 165-171 (1993).

Conversions of R₅ hydroxy and R₈ respectively may be carried out, usingconventional procedures in the art, in particular using the proceduresoutlined in the aforementioned patents.

It should be appreciated that racemates for formula (I) may be resolvedor enantiomerically purified compounds of formula (I) may be preparedusing procedures conventional in the art and in particular using theprocedures outlined in EP-0430631 and EP-0355584.

It should also be appreciated that it is preferred that the compounds offormula (I) may be prepared in the required enantiomeric form by forminga chirally pure epoxide using catalysts and conditions generallyoutlined in WO91\14694 or WO 93\17026 and thereafter converting theepoxides to the required compound of formula (I) using proceduresoutlined herein.

The trans compounds of formula (I) may further be prepared according tothe procedures outlined in PCT/GB92/01045 which procedures areincorporated herein by reference or the trans compounds of formula (I)may be prepared according to methods analogous to these described in theone mentioned patents.

The trans compounds of formula (I) in which R₅ is hydroxy, R₆ is C₁₋₂alkyl and R₉ is hydrogen may be prepared according to the proceduresoutlined in R. Gericke et al. J. Med. Chem. Vol.34, p3074(1991).

The following compounds were prepared by methods analgous to thosedescribed in the abovementioned patents and publications.

The following descriptions, examples and pharmacological test resultsillustrate the present invention:

DESCRIPTION 1

trans-6-Acetyl-4-amino-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3-ol

A mixture of 4-hydroxy-3-iodoacetophenone (5.24 g), 40% sodium hydroxidesolution (4.8 ml), water (19 ml), xylene (11 ml) and3-chloro-3-methylbut-1-yne (4.1 g) was heated to 90° C. for 3 hrs. Themixture was cooled and extracted with ether, and the ether extracts werewashed with 2N sodium hydroxide solution, water and brine and dried overanhydrous sodium sulphate. The ethereal solution was filtered andevaporated, and the xylene solution that remained was refluxed for 16hrs. The solution was evaporated and the residue chromatographed onsilica gel using 10% ethyl acetate in hexane to give6-acetyl-8-iodo-2,2-dimethyl-2H-1-benzopyran as a colourless solid (3.07g), m.p. 102° C.

To a stirred mixture of the benzopyran (2.4 g) in dimethyl sulphoxide(24 ml) and water (0.17 ml) was added NBS (1.56 g) in one portion. Thesolution was stirred for 2 h, and then poured into water. Extraction viaethyl acetate gave a crude bromohydrin (2 g) which was heated to 100° C.in a solution of 2M ammonia in dry methanol in a sealed steel containerfor 16hrs. Aqueous work-up gave the aminoalcohol (0.81 g) of description1, together with unchanged starting material (1.0 g).

EXAMPLE 1

trans-6-Acetyl-4-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3-ol

To a stirred solution of 3-azidobenzoic acid (161 mg) in DMF (5 ml) wasadded ethyl dimethylaminopropyl carbodimide hydrochloride (211 mg) and1-hydroxybenzotriazole (149 mg). The mixture was stirred for 0.5 hr, theaminoalcohol of description 1 (361 mg) added, and stirring continued foran additional 4 hr.

The solution was diluted with ethyl acetate and washed with 1M.HCI,saturated sodium bicarbonate solution, water and brine, and dried overanhydrous sodium sulphate. Filtration and evaporation gave a crudeproduct that was chromatographed on silica gel and eluted with 25% ethylacetate-hexane and recrystallised from ethyl acetate-hexane to give thecompound of example 1 (370 mg); mp 156° C.

DESCRIPTION 2

trans-6-Acetyl-4-amino-3,4-dihydro-2.2-dimethyl-2H-pyrano 2,3-b!pyridin-3-ol

To a solution of 6-bromo-2,2-dimethyl-2H-pyrano 2,3-b!pyridine (1.2 g,prepared as in Synthetic Communs. 18, 1111 (1988)) in dry ether (30 ml)at -78° C. under Argon, was added dropwise a 2.5M solution of n-BuLi inhexanes (2 ml) over 5 min. followed by N,N-dimethylacetamide (0.55 ml).The resulting solution was stirred and allowed to attain roomtemperature. Saturated ammonium chloride solution (2 ml) was added tothe solution. Extraction via ethyl acetate gave a crude solid (0.93 g)which was flash chromatographed on silica gel using ethyl acetate-hexane(3:7) as eluant to give acetylpyranopyridine (0.62 g) as a colourlesssolid.

The aminoalcohol was prepared from the acetylpyranopyridine in a similarmanner to that described in description 1.

EXAMPLE 2

trans-6-Acetyl-4-(2-chlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-pyrano2,3-b!pyridin-3-ol

The aminoalcohol of description 2 was coupled with 2-chlorobenzoic acidin a similar manner to that described in example 1 to give the compoundof example 2 which was recrystallised from acetone. m.p. 243°-244° C.

EXAMPLE 3

trans-6-Acetyl-4-(2,3-dichlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-pyrano2, 3-b!pyridin-3-ol m.p. 257°-258° C.

EXAMPLE 4

trans-6-Acetyl-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethy-8-nitro-2H-1-benzopyran-3-ol

The appropriate aminoalcohol was prepared from4-hydroxy-3-nitro-acetophenone as in description 1, and coupled with4-fluorobenzoic acid as in example 1, to give the compound of example 4;m.p. 212° C.

DESCRIPTION 3

8-Acetyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran

8-Acetyl-2,2-dimethyl-2H-1-benzopyran was prepared from2-hydroxy-acetophenone in a similar manner to that described indescription 1, except that thermal cyclisation of the intermediatepropargyl ether was effected by refluxing in a solution of xylene, DMFand N, N-diethylaniline. Treatment with NBS/H₂ O and ring closure of theresulting bromohydrin with potassium hydroxide pellets in ether gave theepoxide of description 3.

EXAMPLE 5

trans-8-Acetyl-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

4-Fluorobenzamide (0.77 g) was added to a stirred solution of theepoxide of description 3 (0.60 g) in t-butanol (18 ml). Potassiumt-butoxide was added portionwise to the above solution and stirred for 3hrs at room temperature under Argon. The solution was stirred for anadditional 3 hrs at 45° C., cooled, and poured into saturated aqueousammonium chloride and extracted with ethyl acetate. The organic phasewas washed with water and brine and dried over anhydrous sodiumsulphate. Filtration and evaporation and chromatography on silica gel,gradient eluting with pentane to 60% ethyl-pentane gave a yellow solidwhich was recrystallised from ethyl acetate to give the compound ofexample 5 as lemon-white crystals (0.15 g) of m.p. 263°-264° C.

EXAMPLE 6

trans-8-Bromo-4-(3-bromo-4-fluorobenzoylamino)-6-ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

trans-4-(3-Bromo-4-fluorobenzylamino)-6-ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol(800 mg) and mercuric acetate (701 mg) were heated in glacial aceticacid (10 ml) to 100° C. A solution of bromine (0.113 ml) in glacialacetic acid (5 ml) was added to the heated solution during 15 mins, andthe reaction mixture heated for a further 1.5 hrs. The solution wascooled and evaporated and the residue partitioned betweendichloromethane and water. The organic layer was washed with brine anddried over anhydrous magnesium sulphate. Filtration and evaporation andradial chromatography (chromatotron, gradient elution 10%dichloromethane--50% dichloromethane in hexane) gave the compound ofexample 6 (110 mg) as a pale solid of m.p. 70° C.

DESCRIPTION 4

5-Acetyl-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran

3-Hydroxyacetophenone (25 g), sodium hydroxide pellets (11.0 g), 40%benzyltrimethylammonium hydroxide in methanol (38.7 g), and3-methyl-3-chorobut-1-yne (56.4 g) were stirred in water (200 ml) anddichloromethane (200 ml) for 7 days at room temperature. The layers wereseparated and the organic phase evaporated. The aqueous layer wasextracted with ether and this organic extract combined with the residuefrom the evaporation of the dichloromethane phase, and washed with dilsodium hydroxide solution. The ether solution was dried over anhydrousmagnesium sulphate, filtered and evaporated to leave a residue (25 g).

The crude propargyl ether (25 g) was refluxed in o-dichlorobenzene (60ml) for 1.5 hrs. Evaporation and dry flash chromatography (3 times) onsilica gel using dichloromethane-hexane as eluant gave the5-acetylbenzopyran (2.8 g). Treatment of this acetyl compound (2.356 g)with NBS (2.314 g) and water (0.208 ml) in DMSO (30 ml), followed byaddition to water and extraction via ethyl acetate gave the bromohydrin(2.0 g). This bromohydrin (2.0 g) was stirred with potassium hydroxidepellets (1.82 g) in ether (150 ml) at room temperature under Argon for 3days. Filtration and evaporation gave the epoxide of description 4 (1.4g).

EXAMPLE 7

trans-5-Acetyl-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

To the epoxide of description 4 (600 mg), dissolved in t-butanol (100ml), was added 4-fluorobenzamide (956 mg), followed by potassiumt-butoxide (771 mg). The reaction mixture was heated at 40° C. for 4days. The mixture was cooled and evaporated, and the residue taken upinto ethyl acetate. The organic solution was washed with water, brineand dried under anhydrous magnesium sulphate. Filtration and evaporationand radial chromatography (cromatotron, using dichloromethane (2→20%) inhexane as eluent) gave a crude product that was recrystallised fromacetone-hexane (40 mg) with a m.p. 175° C.

EXAMPLE 8

trans-6-Acetyl-4S-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3R-ol

The compound was prepared by epoxidising the chromene of description 1with the appropriate Jacobsen catalyst, recrystallisation from ethylacetate hexane gave 6-acetyl-3R,4R-epoxy3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran. Treatment with aqueousamonia at approximately 60° C. and work up and comply with3-azidobenzoic acid as in example 1 gave the compound of example 8. HPLCon chiral cel OD using ethanol 4% hexane showed enantiomeric purity tobe greater than 99.5%

EXAMPLE 9

trans-8-Acetyl-4-(2-chlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.

m.p. 165°-170° C.

EXAMPLE 10

trans-8-Acetyl-4-(3-chlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzopyran-3-ol.m.p. 182°-183° C.

DESCRIPTION 6

Trans-6-Acetyl-4-amino-3,4-dihydro-2,2-dimethyl-8-(2-phenylethenyl)-2H-1-benzopyran-3-ol##STR2##

A solution of the aminoalcohol of description 1 (250 mg), styrene (88mg), triethylamine (700 mg), tri-o-toluene phosphine (22 mg) andpalladium (II) acetate (8 mg) in anhydrous acetonitrile (3 ml) underargon was heated at 80° C. for 20 h. The reaction mixture was allowed tocool to room temperature and evaporated to dryness. Silica gelchromatography, eluting with ethanol (5-10%) in ethyl acetate gave thedesired product as a solid (150 mg).

DESCRIPTION 7

Trans-6-Acetyl-4-amino-3,4-dihydro-2,2-dimethyl-8-(2-phenylethyl)-benzo-2H-1-pyran-3-ol##STR3##

A solution of description 6 (150 mg) and 10% palladium on carbon (10 mg)in ethanol (5 ml) was allow to stir under hydrogen at atmosphericpressure and room temperature for 36 h. The reaction mixture wasfiltered through a pad of celite and the filtrate evaporated to givecrude mixture of desired product and starting material (150 mg).

EXAMPLE 11

Trans6-Acetyl-4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethyl)-2H-1-benzopyran-3-ol

A solution of the mixture of description 7 (150 mg), 4-fluorobenzoylchloride (70 mg) and diisopropyl ethylamine (57 mg) in dichloromethane(10 ml) was allowed to stir at room temperature for 3 h. The resultingmixture was purified by silica gel chromatography, eluting with ethylacetate (30%) in hexanes to furnish example 11 (30 mg) mp 197°-198° C.

EXAMPLE 12

Trans6-Acetyl-4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethenyl)-2H-1-benzopyran-3-ol

This example (75 mg) was obtained from the mixture obtained in example11 with mp 239° C.

DESCRIPTION 8

6-Hydroxy-1-tetralone

A solution of 6-methoxy-1-tetralone (6.0 g, 0.034 moles) in 48% aqueoushydrobromic acid (80 cm³) was refluxed for 2.5 h. The clear orangesolution was then cooled to ice temp. and the resulting preicpitate wasfiltered off under suction, washed with cold water, and dried to affordthe title compound as a pale orange solid (5.16 g, 93%), δ_(H) 250 MHz:(CD₃)₂ SO! 1.99 (2H, m), 2.47 (2H, t), 2.82 (2H, t), 6.64 (1H, d), 6.71(1H, dd), 7.73 (1H, d) and 10.31 (1H, broad s, OH).

DESCRIPTION 9

6-(methoxyethoxymethoxy)-1-tetralone ##STR4##

A solution of the phenol (description 8) (2.13 g, 0.0132 moles) in dryDMF (18 cm³) was added dropwise to a suspension of sodium hydride (80%dispersion in oil, 0.435 g, 0.0145 moles) in dry DMF (14 cm³) cooled toice temp. under argon. After 10 min a solution of 2-methoxyethoxymethylchloride (1.64 g, 0.0132 moles) was added dropwise. The mixture wasstirred at room temp. for 3 h, poured onto water and extracted twicewith ethyl acetate. The organic extracts were combined and washed(brine), dried and concentrated to afford the title compound as anorange oil 3.2 g, 97%), δ_(H) (250 MHz: CDCl₃) 2.12 (2H, m), 2.62 (2H,t), 2.93 (2H, t), 3.39 (3H, s, OCH₃), 3.56 (2H, m), 3.82 (2H, m), 5.32(2H, s, OCH₂ O), 6.89 (1H, d), 6.96 (1H, dd) and 8.01 (1H, d).

DESCRIPTION 10

5-Bromo-6-(methoxyethoxymethoxy)-1-tetralone ##STR5##

A solution of potassium bromide (10.95 g, 0.092 moles) and sodiumacetate (8.15 g, 0.099 moles) in water (33 cm³) was added to a solutionof the protected phenol (description 9) (4.62 g, 0.0185 moles) inglacial acetic acid (50 cm³). A solution of bromine (3.14 g, 0.0197moles) in glacial acetic acid (20 cm³) was added dropwise over 10 minsat room temp. The mixture was heated to 50° C. for 3.5 h and thenstirred at room temp. overnight. The yellow solution was concentratedand the residue taken up in ethyl acetate and washed (aqueous sodiumbicarbonate, then brine), dried and evaporated. Chromatography on silicagel, elution with ethyl acetate-pentane gradient afforded the titlecompound (3.18 g, 52%), δ_(H) (250 MHz; CDCl₃) 2.15 (2H, m), 2.61 (2H,t), 3.03 (2H, t), 3.38 (3H, s, OCH₃), 3.55 (2H, m), 3.86 (2H, m), 5.42(2H, s, OCH₂), 7.16 (1H, d) and 8.04 (1H, d).

DESCRIPTION 11

5-Bromo-6-hydroxy-1-tetralone

Trifuloroacetic acid (4 cm³) was added to a stirring solution of theprotected phenol (description 10) (3.40 g, 0.0103 moles) indichloromethane (40 cm³) cooled to ice temp. Stirred for 0.5 h at 0° C.and then for 3 h at room temp. The mixture was neutralised on aqueoussodium bicarbonate and separated. The aqueous layer was extracted withethyl acetate. The organic layers were each washed (separately) withbrine, then combined and dried. Concentration afforded the titlecompound as a cream-coloured solid (2.5 g, 100%), δ_(H) (250 MHz; (CD₃)₂SO! 2.01 (2H, m), 2.50 (2H, t, overlapped by (CD₃)₂ SO signal), 2.94(2H, t), 6.94 (1H, d), 7.79 (1H, d), and 11.22 (1H, s, AROH).

DESCRIPTION 12

10-Bromo-2,2-dimethyl-6-oxo-6,7,8,9-tetrahydronaphthaleno 3,2-b!pyrene##STR6##

A solution of sodium hydroxide (1.2 g, 0.03 moles) in water (24 cm³) wasadded to a stirring suspension of the phenol (description 1) (2.5 g,0.0104 moles) and 3-chloro-3-methyl-but-1-yne (2.4 g, 0.0234 moles) inxylene (24 cm³), The mixture was heated to 70° C. for 2.3 h, cooled,poured onto aqueous ammonium chloride and extracted twice with ethylacetate. The extracts were washed (brine), dried and concentrated.Re-dissolved in N,N-dimethylformamide (20 cm³) and heated to 140° C. for20 h. Poured onto water and extracted with diethyl ether. Washed(brine), dried and concentrated. Chromatography on silica ge. elutionwith ether-pentane gradient gave the title compound as a yellow solid(0.40 g, 13%). δ_(H) (250 MHz; CDCl₃) 1.51 (6H, s), 2.13 (2H, m), 2.59(2H, t), 2.98 (2H, t), 5.69 (1H, d), 6.33 (1H, d) and 7.70 (1H, s).

DESCRIPTION 13

(±)-trans-3,3,10-dibromo-2,2-dimethyl-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno3,2-b!pyran-4-ol, 6 ##STR7##

The chromene (description 12) (0.27 g, 0.88 mmol) was stirred indimethylsulphoxide (8 cm³) until dissolution was complete, and thenwater (4 drops) was added followed by N-Bromosuccinimide (0.22 g, 1.23mmol). The mixture was kept at room temp. for 0.75 h and thenpartitioned between water and ethyl acetate. The organic phase waswashed (brine), dried and concentrated to afford the title compound as abeige solid (0.34 g, 96%), δ_(H) (250 MHz; CDCl₃) 1.45 (3H, s), 1.71(3H, s), 2.12 (2H, m), 2.60 (2H, t), 2.99 (2H, t), 4.14 (1H, d) 4.94(1H, d) and 8.24 (1H, s).

DESCRIPTION 14

(±)-10-Bromo-3,4-epoxy-2,2-dimethyl-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno3,2-b!pyran

(±cis) ##STR8##

A solution of sodium hydroxide (0.34 g, 8.5 mmol) in water (5 cm³) wasadded to a stirring solution of bromohydrin (description 13) (0.34 g,0.84 mmol) in 1,4-dioxane (25 cm³). The mixture was stirred at roomtemp. for 4 h and then poured onto aqueous ammonium chloride solution.Extracted twice with ethyl acetate. The extracts were combined, washed(brine), dried and then concentrated to give the title compound as apale brown oil (0.272 g, quant.) δ_(H) (250 MHz; CDCl₃) 1.31 (3H, s),1.68 (3H, s), 2.13 (2H, m), 2.61 (2H, m), 3.01 (2H, m), 3.53 (1H, d),3.97 (1H, d) and 8.10 (1H, s).

DESCRIPTION 13

(±)-trans-4-amino-10-bromo-2,2-dimethyl-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno3,2-b!pyran-3-ol ##STR9##

35% aqueous ammonia (12 cm³) was added to a stirring solution of epoxide(description 14)(0.27 g, 0.79 mmol) in ethanol (16 cm³). The mixture wasstirred at room temp. for four days and then concnetrated. Re-dissolvedin 10% methanol-ethyl acetate (50 cm³) and dried over magnesiumsulphate. Evaporation afforded the title compound (0.26 g, 91%). δ_(H)(250 MHz; (CD₃)₂ SO! 1.21 (3H, s), 1.43 (3H, s), 2.03 (2H, m), 2.52 (2H,m, overlapped by (CH₃)₂ SO signal), 2.89 (2H, t), 3.21 (1H, d, partiallyobscured by H₂) signal), 3.58 (1H, d), 5.61 (1H, broad s) and 8.20 (1H,s).

EXAMPLE 13

(±)-10-Bromo-2,2-dimethyl-trans-4-(4-fluorobenzoylamino)-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno3,2-b!pyran-3-ol ##STR10##

A solution of 4-fluorobenzoyl chloride (97 mg, 0.61 mmol) indichloromethane (4 cm³) was added dropwise to a stirring solution ofamino-alcohol (description 15) (0.20 g, 0.59 mmol) and triethylamine (62mg, 0.61 mmol) in dichloromethane (16 cm³) cooled to ice temp. Themixture was stirred at room temp. under argon atmosphere overnight.Poured onto aqueous sodium bicarbonate solution and spearated. Theaqueous was extracted with chloroform. The organic phases were combeind,washed (brine) dried and concentrated. Chromatography on silica gel,elution with 2% methanol-dichloromethane afforded the title compound asa yellow powder (0.21 g, 77%), (Found: C, 57.18; H, 4.57; N, 3.09. C₂₂H₂₁ BrFNO₄ requires C, 57.16; H, 4.58; N, 3.03), δ_(H) (250 MHz; CDCl₃)1.23 (3H, s), 1.51 (3H, s), 2.02 (2H, m), 2.49 (2H, m, overlapped by(CH₃)₂ SO signal), 2.92 (2H, m), 3.82 (1H, q), 5.08 (1H, broad t), 5.82(1H, d) 7.37 (2H, m), 7.70 (1H, s), 799 (2H, m) and 8.82 (1H, d).

DESCRIPTION 16

3-Bromophenylmethyl ethyl ether ##STR11##

To a solution of 3-Bromobenzylalcohol (4.5 g) in dry dichloromethane (30ml) at -40° C., was added dropwise, 2,6-lutidine (3 mL), followed bytriflate anhydride (4.1 mL). The resulting solution was allowed to stirfrom -40° C. to 0° C. during 4 hours. The solution was evaporated todryness in vacuo and then mixed with absolute ethanol (30 mL) andotassium carbonate 96.9 g) for 16 hours at room temperature. Ethanol wasremoved in vacuo and the residue was purified by aqueous extractivework-up using diethyl ether folowed by silica gel chromatography (20%ethyl acetate/hexane) to give product as a folourless oil (4.62 g, 88%).

DESCRIPTION 17

3-Ethoxymethylbenzoic acid ##STR12##

To a solution of description 16 (4.62 g) in dry tetrahydrofuran (40 mL)under argon at -70° C., was added dropwise, a 1.6M solution ofbutyllithium in hexane (17 mL). The resulting solution was then allowedto stir at -20° for 40 minutes before quenched by the addition of carbondioxide solids. The mixture was allowed to warm up to room temperatureand the tetrahydrofuran removed in vacuo. The oily residue was taken upin diethyl ether and extracted with water twice. The combined aqueoussolution was acidified to pH 1 with 5M hydrochloric acid, extracted withethyl acetate twice. The combined ethyl acetate layer was washed withwater and brine and dried over anhydrous sodium sulphate powder. Thesolution was evaporated to dryness in vacuo to afford product as an oilwhich solidified ons tanding (2.31 g).

EXAMPLE 14

Trans-3R,4S-6-Acetyl-4-(3-ethoxymethylbenzoylamino)-3-4-dihydro-8-iodo-2,2-dimethylbensopb!pyran-3-ol ##STR13##

To a stirred solution of description 17 (0.22 g) in drydimethylformamide (5 mL), was added dimethlaminopropyl ethylcarbodiimidehydrochloride (0.21 g) and 1-hydroxybenzotriazole (0.15 g).3R,4S-6-acetyl-4-amino-3,4-dihydro-3-hydroxy-8-iodo-2,2-dimethylbensob!pyran (0.36 g) was added 30 minutes later. The resulting mixture wasallowed to stir for 16 hours before poured into water and extracted withethyl acetate. The organic layer was washed with brine and dried overanhydrous sodium sulphate powder. Evaporated of the solvent gave productresidue which was purified by silica gel chromatography 930% ethylacetate/hexane), followed by recrystallisation from ethyl acetate/hexaneto afford a colourless solid (0.55 g) mp. 162° C.

DESCRIPTION 17

3-acetyloxymethylbenzoic acid ##STR14##

To a solution of 3-acetyloxymethylbenzyl alchohol (prepared byacetylation of 1,3-dihydroxymethylbenzene) (2.92 g) in pyridine (25 mL),was added a solution of tetra-n-butylammonium permanganate (12 g) inpyridine (25 mL) dropwise. The mixture was allowed to stir at roomtemperature for 3 hours and then poured into cold 2M hydrochloric acid(200 mL) containing sodium metabusulfite (10 g). The mixture wasextracted with diethyl ether (150 mL×3). The combined ether solution waswashed with 1M hydrochloric acid, followed by saturated sodiumbicarbonate solution (150 mL×2). The combined alkaline solution wasacidified by addition of hydrochloric acid and then extracted withdiethyl ether (200 mL×2). The combined ether layer was washed with waterand then brine, dried over anhydrous sodium sulphate powder. This ethersolution was concentrated down to 30 mL to give some precipitate whichwas removed by filtration. The remaining filtrate was evaporated todryness to afford product as a colourless solid (1.7 g).

EXAMPLE 15

Trans-3R,4S-6-Acetyl-4-(3-Acetyloxymethylbenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethylbenzolb!pyran-3-ol ##STR15##

To a stirred solution of description 18 (1.03 g) in drydimethylformamide (5 mL), was added dimethylaminopropylethylcarbodiimide hydrochloride (1.02 g) and 1-hydroxybenzotriazole(0.72 g). 3R,4S-6-acetyl-4amino-3,4-dihydro-3-hydroxy-8-iodo-2,2-dimethylbenzol b!pyran (1.74 g)was added 15 minutes later. The resulting mixture was allowed to stirfor 3 hours before poured into water and extracted with ethyl acetate.The organic layer was washed with brine and dried over anhydrous sodiumsulphate powder. Evaporated of the solvent gave product residue whichwas purified by silica gel chromatography (50% ethyl acetate/hexane),followed by recrystallisation from ethyl acetate/hexane to afford acolourless solid (1.85 g) mp. 167° C.

EXAMPLE 16

Trans-3R,4S-6-Acetyl-3,4-dihydro-4-(3-hydroxymethylbenzoylamino)-8-iodo-2,2-dimethylbenzob!pyran-3-ol ##STR16##

To solution of example 15 (0.82 g) in p-dioxane, was added a 1M solutionof lithium hydroxide in water (2 mL). The solution was allowed to stirfor 2.5 hours before poured into water (150 mL). The precipitate wascollected by filtration, air-dried and recrystallised from hot ethylacetate to afford product as colourless solid crystalline (0.72 g) mp.222° C.

DESCRIPTION 19

(±)-trans-4-amino-2,2-dimethyl-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno3,2-b!pyran-3-ol ##STR17##

A solution of description 15 (1.32 g, 3.88 mmol) in ethanol (50 cm³) washydrogenated over 5% Palladium on charcoal (0.30 g) under 1 atmosphereof hydrogen and at room temperature for a total of 60 hours, refreshingthe catalyst as necessary. The mixture was filtered through kieselguhr,washing the residues with ethanol. The filtrate was then evaporated toafford the title compound as a yellow solid (0.84 g, 83%). δ_(H) 250MHz,(CD₃)₂ SO! 1.13(3H,s), 1.42(3H,s) 2.00(2H, m), 2.54 (2H, m, partiallyobscured by (CH₃)₂ SO signal), 2.88(2H,t), 3.59(1H,q), 4.22(1H,d),6.28(1H,d), 6.79(1H,s), 8.20(1h,S) AND 8.45 (2H, broad s, NH₂).

EXAMPLE 17

(±)-2,2-dimethyl-trans-4-(3-chloro-4-fluorobenzoylamino-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno3,2-b! pyran-3-ol ##STR18##

1-ethyl-3-(3-dimethylaminopropyl)carbodaminde hydrochloride (0.65 g,3.39 mmol) was added to a stirring solution of 3-chloro-4-fluorobenzoicacid (0.59 g, 3.38 mmol) and 1-hydroxybenzotriazole hydrate (0.45 g,3.34 mmol) in dry N,N-dimethylformamide (DMF) (20 cm³). After stirringat room temperature under an atmosphere of argon for 0.5 h,triethylamine (0.34 g, 3.36 mmol) was added. A solution of theamino-alcohol, (description 19), in dry DMF (25 cm³) was then added andstirring was combined for a further 2.5 h. The mixture was poured ontobrine and extracted twice with ethyl acetate. The organic extracts werecombined and washed (water, brine), dried and concentrated,chromatography on silica gel, elution with ethyl acetate-pentanegradient afforded the title compound, which was recrystallised from anethyl acetate-hexane mixture to give a yellow powder (0.52 g, 39%).δ_(H) (250 MHz; CDCl₃) 1.30 (3H,S), 1.53(3H,S), 1.98(2H,m), 2.20(1H,m),2.48(1H,m), 2.78(2H,m), 3.75(1H,dd), 4.32(1H,d), 5.22(IH,t), 6.66(1H,S),7.13(1H,S), 7.45(1H,d), 7.82(1H,m), 7.88(1H,S) and 8.07(1H,dd).

EXAMPLE 18

trans-6-Acetyl-3,4-dihydro-2,2-dimethyl-4S-(3-chlorobenzoylamino)-8-iodo-2H-benzob!pyran-3R-ol ##STR19##

A solution of the amino alcohol (description 1) (500 mg; 1.38 mmol) indry dichloromethane (15 ml) containing dry triethylamine (0.4 ml) wastreated with 3-chlorobenzoyl chloride (314 mg; 1.79 mmol).Recrystallization of the product from ethyl acetate-n-hexane gave thetitle compound as white crystals (475 mg; 69%).

m.p. 171°-30° C. ^(m) /z: 499 (M⁺ ; 1%), 466 (15), 329 (10), 139 (100),111(77)

DESCRIPTION 20

cis 8-Acetyl-2-(3-chlorophenyl)-3a,9b-dihydro-4,4-dimethyl-6-iodo-4H-1-benzol b!pyran 4,3-d!oxazole##STR20##

A solution of the benzamide (example 18) (2.2 g; 4.41 mmol) in drydichloromethane (50 ml) was treated with DAST (0.76 ml; 5.73 mmol) andthe mixture kept at room temperature for 1 day. Evaporation in vacuogave a pale gum which was chromatographed on Kieselgel 60 in 20% ethylacetate/n-hexane. Combination of appropriate fractions gave the titlecompound as a colourless gum (1.6 g; 75%).

v max: 2982, 2916, 1682, 1644, 1596, 1573, 1267 and 715 cm⁻¹

Found M⁺ 482.990976 calc. for C₂₀ H₁₇ NO₃ I³⁷ C1 482.993903

M⁺ 480.995986 calc. for C₂₀ H₁₇ NO₃ I³⁵ C1 480.994173

DESCRIPTION 21

cis8-Acetyl-2-(3-chlorophenyl)-3a,9b-dihydro-4,4-dimethyl-6-hydroxymethyl-4H-benzolb!pyrano 4,3-d!oxazole ##STR21##

A solution of the 8-iodo-oxazoline (description 20) (1.00 g; 2.07 mmol)in dry 1,3-dixoan (8 ml) was treated with tributyltinmethanol (766 mg;2.39 mmol; prepared using method W. Clark Still et al, J. Am. Chem. Soc,1978 100 1481) and tetrakis (triphenylphosphine) palladium (200 mg)under an argon atmosphere. The mixture was heated at 80° C. withstirring under argon for 1 day and then evaporated to dryness in vacuo.The black residue was dissolved in acetonitrile (30 ml) and washed withn-hexane (3×20 ml); evaporation of the acetonitrile layer gave a lighttan gum (1.1 g). Chromatography on Kieselgel 60 in 15%-30% ethylacetate/n-hexane gave pure title compound as a pale yellow gum (560 mg;70%).

¹ H NMR in CDCl₃ δ: 1.38 and 1.61 (2×3H, S), 2.50 (3H,s) 2.11 (1H, t,collapses with D₂ O), 4.70 (2H, d, collapses to s with D₂ O), 4.80 and5.38 (2H, ABq), 7.33 (1H, t), 7.45 (1H, dd), 7.77-8.00 (3H, m) and 8.09(1H,d).

EXAMPLE 19

cis6-Acetyl-4S-(3-chlorobenzoylamino)-3,4-Dihydro-2,2-dimethyl-8-hydroxymethyl-2H-benzolb!pyran-3S-ol ##STR22##

The foregoing oxazoline (description 21) (540 mg; 1.45 mmol) in1,4-dioxan (15 ml), water (5 ml) and 5n H₂ SO₄ (2 ml) was kept at 25° C.for 2 days. An excess of solid NaHCO₃ was added and the suspensionstirred for 2 h. Evaporation in vacuo followed by partition betweenethyl acetate and water gave the product from the organic phase.Recrystaliisation from dichloromethane/hexane/methanol afforded thetitle compound was white crystals (355 mg; 88%) m.p. 217°-9° C.

v max: 3332, 2900, 1668, 1650, 1604, 1520 and 746 cm⁻¹

EXAMPLE 20

cis8-Acetoxymethyl-6-acetyl4S-(3-chlorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzob!pyran-3S-ol ##STR23##

A solution of alcohol (example 19) (120 mg; 0.3 mmol) in dry THF (6 ml)containing acetic anhydride (45 mg; 0.44 mmol) and dry triethylamine(0.1 ml) was heated at 80° under argon for 20 h. Evaporation in vacuogave a pale yellow gum which was chromatographed on Kieselgel 60 in15-30% ethyl acetate/n-hexane. Combination of appropriate fractions gavethe title compound as white crystals (57 mg; 43%).

m.p. 172°-173.5° C. (from ethyl acetate/pentane)

^(m) /z: CI⁺ 463 (MNH₄ +, 100%), 446 (MH⁺, 6%).

EXAMPLE 21

Trans-6-Acetyl-4-(4-fluorobenzoylamino-3,4-dihydro-2,2,7-trimethyl-2H-1-benzopyran-3-ol

Crystals of m.p. 162°-163° C. from ethyl acetate-petrol.

¹ H NMR (250 MHz) CDCl₃ δ:1.32 (3H, s), 2.47 (6H, s), 3.74 (1H,dd), 4.29(1H, d), 5.26 (1H, t), 6.58 (1H, s), 6.70 (1H, s), 7.16 (2H, t), 7.68(1H, s), 7.87 (2H,m).

EXAMPLE 22

trans-6-Acetyl-7-fluoro-4-(4-fluorobenzoylamino)-3,4dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol

Crystals of m.p. 200°-203° C. from ethyl acetate-hexane.

¹ H NMR (250 MHz) CDCl₃ δ: 1.32 (3H, s), 1.52 (3H, s), 2.55 (3H, d),3.78 (1H,dd), 4.75 (1H, d), 5.21 (1H, t), 6.58 (1H, d), 7.11 (2H, t),7.76 (1H, d, NH), 7.85 (1H, d), 7.96 (2H, m).

PHARMACOLOGICAL DATA

1. Rat Social Interaction Test

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may be tested for therapeutic utility using the procedureoutlined as follows:

Potential anxiolytic properties are evaluated using the rat socialinteraction procedure based on that originally described by File (1980,J. Neurosci. Methods, 2, 219-238). In this model anxiolytic agentsselectively increase social interaction independently of any effect onlocomotor activity.

Method

Male Sprague--Dawley rats (Charles River. U.K., 250-300 g) are singlyhoused for 3 days prior to testing. On the test day, the animals arethen randomly assigned to groups of 8-16 and dosed orally at a dosevolume of 1 ml/kg with various doses of compound (1-300 mg/kg) orvehicle. At 60 min post dose the rats are placed with a weight- andtreatment-matched pair male (encountered for the first time) in thesocial interaction box under high - light, unfamiliar conditions. Thebox is made of white perspex 54×37×26 cm with a transparent perspexfront side. The floor is divided into 24 equal squares and is brightlylit (115 lux). Time spent (secs) in active social interaction (sniffing,grooming, following, mounting, climbing over or under, boxing, biting)is scored "blind" by remote monitoring as is the number of squarescrossed (as an index of locomotion).

The mean and standard error for time spent in social interaction andnumber of squares crossed are then calculated for each particulartreatment group and drug-induced changes are expressed as a percentageincrease or decrease from control values. Statistical comparisons aremade between vehicle- and drug-treated groups using Dunnett's multiplecomparisons procedure following significant one way analysis ofvarience.

Drugs are suspended in 1% methyl cellulose.

2. MES TEST

The maximal electroshock seizure (MES) threshold test in rodents isparticularly sensitive for detecting potential anticonvulsantproperties¹. In this model, anticonvulsant agents elevate the thresholdto electrically-induced seizures whilst proconvulsants lower the seizurethreshold.

Method

Mice (male, Charles River, U.K. CD-1 strain, 25-30 g) are randomlyassigned to groups of 10-20 and dosed orally or intraperitoneally at adose volume of 10 ml/kg with various doses of compound (0.3-300 mg/kg)or vehicle. Mice are then subjected at 30 or 60 min post dose to asingle electroshock (0.1 sec, 50Hz, sine wave form) administered viacorneal electrodes. The mean current and standard error required toinduce a tonic seizure in 50% (CC₅₀) of the mice in a particulartreatment group is determined by the `up and down` method of Dixon andMood (1948)². Stastical comparisons between vehicle- and drug-treatedgroups are made using the method of Litchfield and Wilcoxon (1949)³.

In control animals the CC₅₀ is usually 14-18 mA. Hence the first animalin the control group is subjected to a current of 16 mA. If a tonicseizure does not ensue, the current is increased for a subsequent mouse.If a tonic convulsion does occur, then the current is decreased, and soon until all the animals in the group have been tested.

The percentage increase or decrease in CC₅₀ for each group compared tothe control is calculated.

Studies are carried out using a Hugo Sachs Electronik Constant CurrentShock Generator with totally variable control of shock level from 0 to300 mA and steps of 2 mA are usually used.

Drugs are suspended in 1% methyl cellulose.

References

1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181

2. Dixon, W. J. and Mood, A. M. (1948). J. Amer. Stat. Assn., 43,109-126

3. Litchfield, J. T. and Wilcoxon, F.(1949). J. Pharmacol. exp. Ther.,96, 99-113

Results

The compound of example 6 enhanced seizure threshold by 84% at 30 mg/kgp.o.

3. X-Maze

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may be tested for therapeutic utility using the procedureoutlined as follows:

Introduction

The X-maze test of anxiety (Handley and Mithani, 1984) examines theexploratory response of naive rats in an environment which offers bothanxiogenic (open arms) and relatively non-anxiogenic (closed arms)areas. A selective increase in exploration of the open arms followingdrug pretreatment is therefore postulated to indicate anxiolyticeffects.

Method

The X-maze was raised 70 cm above the floor and consisted of twoenclosed arms 45 cm (long)×15 cm (wide)×10 cm (high) and two open arms45×10×1 cm arranged such that the two arms of each type were oppositeeach other. Both arm types are marked into two equal sections. Rats areplaced onto the centre of the X-maze and observed for a period of 10minutes during which time the following parameters were recorded: 1) thenumber of entries onto, and the time spent on, (a) open arms, (b) closedarms, (c) end of open arms and (d) end of closed arms. 2) the number ofsections crossed. The fear-drive evoked in the open arms exceeds that inthe enclosed arms and rats typically show a clear preference for theenclosed arms. Anxiolytic drugs increase the number of entries madeonto, and the time spent on, the outer half of the open arms, and alsothe percentage of entries made onto, and the time spent on, the whole ofthe open arms. These four measures of anxiety, and also the total numberof sections traversed, were calculated for each animal. Drugs areadministered intraperitoneally or orally to groups of 6 to 12 rats 30 to60 mins before testing. Statistical comparisons between vehicle- anddrug-treated groups were made using a Mann-Whitney `U` test (twotailed).

S. L. Handley and S. Mithani, Arch. Pharmacol., 1984 327 1-5

4. Mongrel Dog Delayed Cerebral Vasospasm

The compounds of formula (I) includingcis-4-benzoylamino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzob!pyran-3-ol or pharmaceutically acceptable salts thereof may be testedfor therapeutic utility using the procedures outlined as follows:

Twenty-five male mongrel dogs, weighing 9-12 kg, are used in thesestudies. The animals are housed and cared for in accordance with theGuide for the Care and Use of Laboratory Animals DHEW (DHHS) publicationNo. (NIH) 85-23, revised 1985!. All procedures using laboratory animalsare approved by the Institutional Animal Care and Use Committee ofSmithKline Beecham Pharmaceutical. Each animal is anaesthetized withpentobarbital (35 mg/kg, iv) and placed on a heated operating table inthe supine position. All animals are then tracheotomized, paralyzed(tubocurarine; 0.1 mg/kg, i.v.) and artificially ventilated with roomair. End-tidal CO₂ (et CO₂) is monitored continuously and arterial bloodgas analysis was performed periodically to assure stable and adequateventilation throughout each experiment. Polyethylene cannulae are placedin the left external jugular vein and the right femoral artery and veinfor drug administration, monitoring arterial blood pressure, and bloodsampling, respectively. Transfemoral catheterization of the leftvertebral artery is then performed via the left femoral artery using a 5french Lehman dacron catheter (Bard, Tewksbury Mass.). Anaesthesia issupplemented as needed with pentobarbital (5 mg/kg, i.v.) prior to theexperimental period.

The effects of the compounds of this invention on acute cerebralvasospasm are evaluated in 15 dogs. In all animals a control digitalsubtraction angiogram of the anterior spinal artery and basilar arteryis obtained following the intravertebral injection of radiocontrastmaterial (Omnipaque 300). In each dog, 4 mls of cerebrospinal fluid isthen removed from the dorsal cistern via needle puncture of theatlantooccipital membrane and 4 mls of autologous venous blood wasinjected. An angiogram is then repeated in each dog 30 minutes followingthe intracisternal administration of blood and an acute vasospasm of thebasilar and anterior spinal arteries is identified and quantitated. Theinfusion of vehicle (10% polyethylene glycol 200) for 30 minutes has noeffect on the acute vasospasm. The effect of a 30 minute infusion oftest compounds on the reversal of acute vasospasm is observed in thebasilar and anterior spinal arteries.

The effects of the compounds of this invention are also examined in thechronic canine model of delayed cerebral vasospasm (two haemorrhagemodel of cerebral vasospasm). In this model, a control vertebralangiogram is obtained and autologous blood is administeredintracisternally on day 1 (as above). On day 3 the intracisternaladministration of blood is repeated and the severe delayed vasospasm isquantitated angiographically on day 7 in all animals. The infusion ofvehicle (10% polyethylene glycol 200) for 60 minutes has no effect onthe delayed vasospasm observed in the basilar and anterior spinalarteries (n=5). The effect of an infusion of test compounds on thereversal of significantly delayed cerebral vasospasm indicates that thecompound is active.

5. The compounds of formula (I) or pharmaceutically acceptable saltsthereof may be tested for therapeutic utility using the proceduresoutlined as follows:

1) Anti-Parkinsonian Activity

6- Hydroxydopamine-lesioned rat model

The above test as described by Ungerstedt, U. 1971, Acta Physiol. Scand367, 49-68, and/or Ungerstedt, U, 1971, Acta Physiol Scand. 367, 69-93,may be used to determine the anti-Parkinsonian activity of compounds offormula(I) or pharmaceutically acceptable salts thereof.

2) Anti-Psychotic Activity

Amphetamine-induced rat hyperlocomotion model

The above test as described by Kokkindis L, and Anisman, M, 1980,Psychological Bulletin, 88, 551-579, may be used to determine theanti-psychotic activity of compounds of formula (I) or pharmaceuticallyacceptable salts thereof.

3) Anti-Migraine Activity

Cortical Spreading Depression and Migraine

The above test as described by Wahl et al, 1987, Brain Research, 411,72-80 may be used to determine the anti-migraine activity of compoundsof formula (I) or pharmaceutically acceptable salts thereof.

4) Cerebral ischaemia

a) Mongolian Gerbil Test

The in vivo experiments are carried out on adult Mongolian gerbils(Tumblebrook Farm (Mass.). weighing 60-80 g. Transient forebrainischemia is produced by bilateral carotid artery ligation under 2.5%isoflourane in 100% O₂ anesthesia, the animals being placed onto aheating pad to maintain body temperature at 37° C. The common carotidarteries are exposed and aneurism clips are placed on both arteries fora certain period of time indicated in the figure legends. PBN dissolvedin saline was administered intraperitoneally as a bolus 30 min beforeocclusion (pretreatments) or immediately after and again at 6 h ofreperfusion, followed by the same dose b.i.d. for 2 days(post-treatment). For quantification of CA1 neurons, animals aresacrificed at 7 days postischemia and perfused with buffered formalin.Brains were removed, stored in formalin for 3 days, embedded inparaffin, cut at 7μm-thick coronal sections (1.5-1.9 mm posterior tobregma¹⁵) and stained with thionin. The number of intact neurons over a750-μm length of the CA1 layer on both hippocampal sides of 3 sectionsis counted for each animal.

b) MCAO Method

Three strains of mature male rats (SHR) are obtained from commercialvendors (Taconic Farms, Germantown, N.Y.; Charles River, Danyers, Mass.;and

Charles River, respectively) at 18 wk of age (250-300 g in weight) andare housed for 2 to 4 weeks prior to utilization in these studies. Inorder to verify that the strains of animals studied are indeedhypertensive and normotensive, groups of animals from each strain areanesthetized with 2% isoflourane (Anaquest, Madison, Wis.) andchronically prepared under aseptic conditions for recording of bloodpressure. The femoral artery is cannulated with polyethylene tubing(PE60; Clay Adams. Parsippany, N.J.) extending just into the descendingaorta. The tubing is lead subdermally from the artery and exteriorizedbetween the scapula just below the back of the neck and cleared/filledwith sterile isotonic saline. Incisions are closed using 2-0 silk sutureand treated with 5% lidocaine ointment (Astra Pharmaceuticals,Westborough, Mass.) Animals recover from surgery/anesthesia within 5min. Mean arterial blook pressures are recorded 4 to 5 h after surgeryfor 5 min/rat by connecting the exteriorized tubing in each rat to aStatham pressure transducer (P2.3Db; Statham Medical Instruments. LosAngeles, Calif.) with output to a polygraph (Model R711: BeckmanInstruments, Inc., Fullerton, Calif.).

Focal Stroke Procedure

MCAO or sham surgery is carried out in the SHR, SD rats under sodiumpentobarbital (65 mg/kg, i.p. and supplemented as needed) anesthesia.All animals are allowed free access to food and water prior to and aftersurgery. Body temperature is maintained at 37° C. using a heating padthroughout the surgical procedure. Surgery is conducted similar to thatdescribed previously (2.4). The right dorsal surface to the head andshaved and prepped with providone-iodine, and the rat placed in astereotaxic device (David Kopf Instruments, Tujunga, Calif.) with thesurgery (right) side of the head superior. A 1-2 cm incision was madebetween the orbit and the external auditory canal. The temporal muscleis dissected from the skull and retracted without damaging the zygomaticbond or mandibular nerve. Under an operating microscope and with salineirrigation, a 2-3 mm craniotomy is made just rostral to thezygomatic-squamosal skull suture. The dura is opened over the arteryusing the modified tip of a 30-gauge needle. For permanent right MCAO,using electrocoagulation (Force 2 Electrosurgical Generator, Valley LabInc., Boulder, Colo.), the artery was stimultaneously occluded and cutdorsal to the lateral olfactory tract at the level of the inferiorcerebral vain. A small piece of sterile saline-soaked Gelfoam (Upjohn,Kalamazoo, Mich.) is then positioned over the craniotomy and thetemporails muscle and skin are closed in two layers. Animals are allowedto recover from anesthesia under a heating lamp and then are returned totheir cages. The animals are sacrificed 24 hours following MCAO and thebrains are prepared from reactive histologic examination.

Measurements of Ischemic Damage

Following the neurologic evaluation (24 hours after surgery) rats areeuthanized with an overdose of sodium pentobarbital. Within 2-3 min,brains are removed and six coronal forebrain slices (2 mm thick) aremade from the level of the olfactory bulbs to the cortical-cerebellarjunction using a rat brain slicer (59); Zivic-Miller Laboratories Inc.,Allison Park, Pa.!. These forebrain slices then are immersed immediatelyin a 1% solution of triphenyltetrazolium chloride (TTC) in phosphatebuffer at 37° C. for 20-30 min (6.78). Strained tissues then are fixedby filtration in 10% phosphate buffered formalin. The two sides of eachTTC-strained section are photographed in colour using a polaroid camera.These photographs are analyzed for the quantification of ischemic damageusing an image analysis system (Amersham RAS 3000; Loats Associates,Inc.). Morphological changes following surgery are evaluated in theentire forebrain (total of 11 planar surfaces) for each animal. The 11planar images are planar surfaces) for each animal. The 11 planar imageswere obtained from each side of the six 2 mm thick sections andcorrespond approximately to 1 mm section surfaces from +5 mm to -5 mmfrom bregma (97) and include the complete forebrain. These planar imagesurfaces (from the photographs) are digitized and used in the ImageAnalysis System for planimetry determination of infarct size andswelling. Two parameters of ischemic damage due to MCAO are determinedfor each slice as described previously (2,4,98,122). "Hemisphericswelling" is expressed as the percent increase in size of theipsilateral (i.e., surgery side) hemisphere over the contralateral(normal) hemisphere and is calculated as: ##EQU1##

"Infarct size" which was expressed as the percent infarcted tissue inreference to the contralateral (normal) hemisphere and is calculated as:##EQU2##

The swelling and infarct size are expressed in reference to thecontralateral hemisphere (i.e., ipsilateral ischemic damage isnormalized to the normal contralateral hemisphere). These parameters aredetermined for each slice to evaluate the profile of damage throughoutthe forebrain (i.e., "fore-brain profile") and for "total" forebrainchanges by using the sum of all individual slice data in these formulas.The occurrence of brain edema asociated with hemispheric swellingfollowing MCAO was determined by comparison of wet/dry weight asdescribed previously (45,118). Rats were sacrificed by an overdose ofsodium pentobarbital 24 hours after sham or MCAO surgery. The brains arequickly removed, the forebrain isolated at the cerebellar corticaljunction and cut into two hemispheres, and each forebrain hemispheremeasured on a Mettler Types H5 chemical balance (Mettler InstrumentsCorp, Hightstown, N.J.) within 2 min after decapitation. The dry weightwas measured on the same scale after drying the hemisphere in an over at80° C. for 48-72 hours. The water content of each hemisphere wascalculated as the difference between the wet and dry weight as a percentfraction from the wet weight: ##EQU3##

We claim:
 1. A compound which is trans-6-Acetyl-4-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3-ol.
 2. A compound which is trans-8-Bromo-4-(3-bromo4-fluorobenzoylamino)-6-ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.
 3. A compound which is trans-6-Acetyl4S-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3R-ol.
 4. A compound which is trans 6-Acetyl4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethyl)-2H-1-benzopyran-3-ol.
 5. A compound which is trans 6-Acetyl-4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethenyl-)-2H-1-pyran-3-ol.
 6. A compound which is (±)-10-bromo-2,2-dimethyl-trans4-(4-fluorobenzoylamino)-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno 3,2-b!pyran-3-ol.
 7. A compound which is trans-3R,4S-6-Acetyl-4-(3-ethoxymethylbenzoylamino)-3-4-dihydro-8-iodo-2,2-dimethylben° b!pyran-3-ol.
 8. A compound which is trans-3R,4S-6-Acetyl-4-(3-Acetyloxymethylbenzoylamino)-3,4-dihydro-8-iodo-2,2dimethylbenzol b!pyran-3-ol.
 9. A compound which is trans-3R,4S-6-Acetyl-3,4-dihydro-4-(3-hydroxymethylbenzoylamino)-8-iodo-2,2-dimethylbenzo b!pyran-3-ol.
 10. A compound which is (±)-2,2-dimethyl-trans-4-(3-chloro4-fluorobenzoylamino-3,4,6,7,9,9-hexahydro-6-oxo-naphthaleno 3,2-b!pyran-3-ol.
 11. A compound which is cis 6-Acetyl4S-(3-chlorobenzoylamino)-3,4-Dihydro-2,2-dimethyl-8-hydroxymethyl-2H-benzol b!pyran-3S-ol.
 12. A compound which is cis 8-Acetoxymethyl-6-acetyl4S-(3-chlorobenzoylamino)-3,4dihydro-2,2-dimethyl-2H-benzo b!pyran-3S-ol.
 13. A method of treatment of anxiety, mania, depression, the effects associated with withdrawal from substances of abuse, a disorder treatable and/or preventable with anti-convulsive agents, Parkinson's disease, psychosis, migraine, cerebral ischaemia, schizophrenia, OCD, a panic disorder and/or agression in a sufferer, comprising administering to the sufferer in need thereof an effective amount of a compound selected from the group consisting of: trans-6-Acetyl4-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3-ol;trans-8Bromo-4-3-bromo-4-fluorobenzoylamino-6-ethyl-3,4-dihydro-2.2-dimethyl-2H-1-benzopyran-3-ol; trans-6-Acetyl-4S-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl1-2H-1-benzopyran-3R-ol; trans 6-Acetyl4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethyl)-2H-1 -benzopyran-3-ol; trans 6-Acetyl-4-(4-fluorophenylbenzoylamino -3,4-dihydro-2,2-dimethyl-8-(2-phenylethenyl)-2H-1-benzopyran-3-ol; (±)-10-bromo-2,2-dimethyl-trans-4-(4-fluorobenzoylamino)-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno 3,2-b!pyran-3-ol; trans-3R,4S-6-Acetyl4-(3-ethoxymethylbenzoylamino)-3-4-dihydro-8-iodo-2,2-dimethylbenzo b!pyran-3-ol; trans-3R,4S-6-Acetyl4-(3-Acetyloxymethylbenzoylamino)-3,4dihydro-8-iodo-2,2dimethylbenzo b!pyran-3-ol; trans-3R,4S-6-Acetyl-3,4-dihydro-4-(3-hydroxymethylbenzoylamino)-8-iodo-2,2-dimethylbenzo b!pyran-3-ol; (±)-2,2-dimethyl-trans-4-(3-chloro-4-fluorobenzoylamino-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno 3,2-b!pyran-3-ol; cis 6-Acetyl-4S-(3-chlorobenzoylamino)-3,4-Dihydro-2,2-dimethyl-8-hydroxymethyl-2H-benzol b!pyran-3S-ol: or cis 8-Acetoxymethyl-6-acetyl4S-(3-chlorobenzoylamino)-3,4dihydro-2,2-dimethyl-2H-benzo b!pyran-3S-ol or a pharmaceutically acceptable salt thereof.
 14. A pharmaceutical composition comprising a compound selected from the group consisting of:trans-6-Acetyl-4-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3-ol; trans-8-Bromo-4-(3-bromo-4-fluorobenzoylamino)-6-ethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol; trans-6-Acetyl-4S-(3-azidobenzoylamino)-3,4-dihydro-8-iodo-2,2-dimethyl-2H-1-benzopyran-3R-ol; trans 6-Acetyl-4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethyl)-2H-1-benzopyran-3-ol; trans 6-Acetyl-4-(4-fluorophenylbenzoylamino)-3,4-dihydro-2,2-dimethyl-8-(2-phenylethyl)-2H-1-benzopyran-3-ol; (±)-10-bromo-2,2-dimethyl-trans-4-(4-fluorobenzoylamino)-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno 3,2-b!pyran-3-ol; trans-3R,4S-6-Acetyl-4-(3-ethoxymethylbenzoylamino)-3-4-dihydro-8-iodo-2,2-dimethylbenzo b!pyran-3-ol; trans-3R,4S-6-Acetyl-4-(3-Acetyloxymethylbenzoylamino)-3,4-dihydro-8-iodo-2,2dimethylbenzo b!pyran-3-ol; trans-3R,4S-6-Acetyl-3,4dihydro-4-(3-hydroxymethylbenzoylamino)-8-iodo-2,2-dimethylbenzo b!pyran-3-ol; (±)-2,2-dimethyl-trans4-(3-chloro-4-fluorobenzoylamino-3,4,6,7,8,9-hexahydro-6-oxo-naphthaleno 3,2-b!pyran-3-ol; cis 6-Acetyl-4S-(3-chlorobenzoylamino)-3,4-Dihydro-2,2-dimethyl-8-hydroxymethyl-2H-benzo b!pyran-3S-ol; or cis 8-Acetoxymethyl-6-acetyl4S-(3-chlorobenzoylamino)-3,4dihydro-2,2-dimethyl-2H-benzo b!pyran-3S-ol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
 15. The method of claim 13 wherein said substances of abuse are cocaine, nicotine, alcohol and benzotriazines.
 16. The method of claim 13 wherein said disorder treatable and/or preventable with anti-convulsive agents is epilepsy. 